Drug addiction is a chronic, relapsing condition characterized by compulsive drug seeking and substance use despite harmful consequences. Persistent relapse to addictive drugs constitutes the most challenging problem in addiction therapy, and is linked to impaired prefrontal cortex regulation of motivated behaviors that involve the nucleus accumbens. Learning to inhibit drug seeking can be an important strategy to reduce the risk of relapse. Treatments are sought that can aid in these learning processes. Here we will explore vagus nerve stimulation (VNS) as a means to facilitate extinction learning (i.e. the inhibition of a response to a previously learned stimulus) and to reduce reinstatement of drug seeking (relapse) in an animal model of cocaine addiction. Vagus nerve stimulation is a FDA- approved treatment for epilepsy and depression and its mechanisms of action likely involve release of norepinephrine in the cortex and amygdala. The proposed research is based on recent data which show that VNS can induce cortical plasticity and can enhance extinction of fear memories. Because brief VNS affords tight temporal control over neuromodulator release, our approach provides context-specificity and may target the brain areas and synapses that support extinction of drug memories more efficiently than drug-based treatments can. If VNS holds promise as a novel approach to the treatment of drug addiction, the mechanisms of action need to be better understood. We propose the following 3 Aims to test the effects of VNS on extinction training and reinstatement in cocaine self-administering rats: In Aim 1 the effect of VNS on drug extinction training and reinstatement will be investigated in cocaine self- administering rats using a short-access paradigm. In Aim 2 we will study the network that underlies the effect of VNS on operant behavior, and specifically changes in synaptic plasticity (LTP and LTD) in the projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAc) using extracellular local field recordings in-vivo. We predict that combining VNS with extinction training restores the ability to induce LTP in the mPFC-NAc pathway, and that it suppresses the induction of LTD more than extinction training does by itself. These effects should be positively correlated to the inhibition of cocaine seeking produced by extinction. In Aim 3 we will perform patch-clamp recordings from medium spiny neurons in the NAc in vitro and use optogenetic stimulation of identified inputs from the mPFC to further examine changes in glutamate receptor function (measured as changes in the AMPAR/NMDAR current ratio) and alterations in presynaptic release that underlie VNS' effects on metaplasticity in the extinction circuit. The proposed research will test a novel approach to aid consolidation of extinction learning and it will elucidate important basic questions of how a potential therapy works.